Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O.ClCCl>[CH2:40]([NH:47][C:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:9])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1ncsc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ncsc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of 4-methylthiazole-5-carboxylic acid (5.00 g, 34.92 mmol) in anhydrous N,N-dimethylformamide (75 mL) was added 1-hydroxybenzotriazole (5.66 g, 41.91 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (8.04 g, 41.91 mmol), N,N-diisopropylethylamine (18.23 mL, 104.76 mmol) and benzylamine (4.57 mL, 41.91 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (55 mL) and brine (45 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (35-45% ethyl acetate in hexanes) to afford N-benzyl-4-methylthiazole-5-carboxamide as a white solid (4.85 g, 60%): 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 7.36-7.33 (m, 5H), 6.17 (br s, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.72 (s, 3H); MS (ES+) m/z 233.2 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]([CH:13]([CH3:15])[CH3:14])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O.O1CCOCC1>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]([CH:13]([CH3:14])[CH3:15])[NH:12][S:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1)(=[O:34])=[O:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of D-valine benzyl ester hydrochloride (2.4 grams, 10 mmol) and triethylamine (2.5 grams, 3.5 mL, 25 mmol) in water (50 mL) and 1,4-dioxane (50 mL) is added 4-methoxybenzenesulfonyl chloride (2.3 grams, 11 mmol). The mixture was stirred at room temperature for 1 hour and then most of the solvent was removed by evaporation under vacuum. The mixture was diluted with ethyl acetate and was washed successively with dilute hydrochloric acid solution, water and brine. The organic solution was dried over magnesium sulfate and concentrated to leave N-(4-methoxybenzenesulfonyl)-D-valine benzyl ester as a white solid, 3.6 grams (97%); m.p. 92°-94° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[CH3:39][NH:40][CH3:41].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:40]([CH3:41])[CH3:39])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: CNC
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(CCN(C)C)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 13.3 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.080 g, 0.15 mmol), dimethylamine (2.0 M in THF, 0.07 mL, 0.15 mmol), triethylamine (0.021 mL, 0.15 mmol), and sodium iodide (0.021 g, 0.15 mmol) in DMF (2.5 mL) was heated in a resealable tube at 70° C. for 15 h. Additional dimethylamine solution (0.10 mL) was added and the reaction mixture was heated at 70° C. for 20 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration and purified by silica gel column chromatography (elution with 20% MeOH:CH2Cl2 to 10:30:60 Et3N:MeOH:CH2Cl2); the appropriate fractions were combined and concentrated to afford N2-(4-{4-amino-1-[2-(dimethylamino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide as a white solid (0.009 g, 0.02 mmol). RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.52.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:31])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:30]>C1COCC1.O.C(Cl)Cl>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:31])=[O:4])=[C:8]2[CH3:30])(=[O:18])=[O:17])=[CH:20][C:21]=1[O:27][CH2:28][CH3:29])#[N:26]
Reactant: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)OC)c3cccnc32)ccc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1M Lithium hydroxide (57 μl) is added dropwise to a cooled (0° C.) solution of [1-(4-cyano-3-ethoxy-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.024 g, 0.057 mmol) in THF/water (4 ml of a 1:1 mixture). After stirring at 0° C. for 10 minutes, the reaction mixture is stirred at room temperature for 2.5 hours and then diluted with DCM (4 ml). The resulting mixture is passed through a phase separation cartridge and the aqueous portion is acidified to pH 4 with 1M HCl. This portion is extracted with DCM (2×4 ml) and the organic extracts are combined, passed through a phase separation cartridge, and concentrated in vacuo. The resulting solid is dissolved in ethyl acetate (2 ml) and triturated with iso-hexane (7 ml) to yield the titled compound as a white solid. (MH+ 400)
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:41]=[CH:40][C:16]([CH2:17][O:18][C:19](=[O:39])[C@@H:20]2[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19](=[O:39])[C@@H:20]2[CH2:24][C:23](=[O:25])[CH2:22][N:21]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:40][CH:41]=1
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)[C@@H]2CC(=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A soluton of 0.35 ml of dimethyl sulfoxide in 1 ml of dried methylene chloride was added dropwise to a solution of 0.2 ml of oxalyl chloride in 5 ml of dried methylene chloride at -60° to -70° C. Ten minutes later, 10 ml of a dried methylene chloride solution of 860 mg of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester was added dropwise to the above mixture at a temperature of -50° C. or less, followed by stirring for 15 minutes. 1.01 g of triethylamine was then added dropwise thereto, and the resulting mixture was warmed to room temperature. The mixture was diluted with methylene chloride, washed with dilute hydrochloric acid aqueous solution and dried over sodium sulfate. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography to yield 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH:8]2[CH2:12][CH:11]([CH2:13][O:14]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:10]=[CH:9]2)[CH:6]=[CH:5][N:4]=[C:3]1[C:34]([O:36][CH3:37])=[O:35]>C(O)(=O)C.O>[OH:14][CH2:13][CH:11]1[CH2:12][CH:8]([N:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:34]([O:36][CH3:37])=[O:35])[C:2]2=[O:1])[CH:9]=[CH:10]1
Reactant: COC(=O)c1nccn(C2C=CC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nccn(C2C=CC(CO)C2)c1=O
Temperature: 80 °C
Yield: 75.8 %

Procedure:
In 2.0 mL of 80% aqueous solution of acetic acid was dissolved 0.20 g of methyl 3-oxo-4-{4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-3,4-dihydro-2-pyrazinecarboxylate, and the solution thus obtained was heated at 80° C. for one hour. The reaction mixture was allowed to cool and diluted with 10 mL of water, the deposited precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [eluent: ethyl acetate] to obtain 77 mg of methyl 4-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a light yellow oily product.
Reaction SMILES: COC1C=C(CC(O)C)C=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH:19]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:18]2.[Br:32]Br.C1CCN2C(=NCCC2)CC1>CC#N>[C:21]1(=[O:25])[C:22]2[C:17](=[CH:16][CH:15]=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH2:20]1.[Br:32][C:20]1[C:19]([CH2:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=2)[C:21]=1[OH:25]
Reactant: COc1ccc2c(c1)CC(CCC(F)(F)F)CC2=O
Reactant: BrBr
Agent: COc1cccc(CC(C)O)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(O)c(Br)c(CCC(F)(F)F)cc2c1
Product: O=C1CCCc2ccccc21

Procedure:
Treatment of 6-(methyloxy)-3-(3,3,3-trifluoropropyl)-3,4-dihydro-1(2H-naphthalenone (121) (0.40 g, 1.47 mmol) with bromine followed by DBU in CH3CN gave 0.47 g (92% from tetralone) of the title compound (122) as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.40-2.55 (m, 2H), 3.05-3.10 (m, 2H), 3.91 (s, 3H), 6.06 (s, 1H), 7.02 (d, J=2.5 Hz, 1H), 7.12 (dd, J1=9.1 Hz, J2=2.5 Hz, 1H), 7.20 (s, 1H), 8.10 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 347 (M−H)−.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].NC1[CH:15]=[C:16]([CH:20]([CH3:23])[C:21]#[N:22])[CH:17]=[CH:18]C=1.NC1C=[CH:41][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[N:31]=2)=[CH:27][CH:26]=1>ClCCl>[C:21]([CH:20]([CH3:23])[C:16]1[CH:15]=[C:12]([NH:8][C:1]([NH:3][C:7]2[CH:6]=[CH:41][C:28]([O:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[N:31]=3)=[CH:27][CH:26]=2)=[O:2])[CH:11]=[CH:18][CH:17]=1)#[N:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: CC(C#N)c1cccc(N)c1
Solvent: ClCCl
Product: CC(C#N)c1cccc(NC(=O)Nc2ccc(Oc3ccnc(NCCCO)n3)cc2)c1
Reaction time: 12 h

Procedure:
222 mg (1.37 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 182 mg (1.24 mmol) 2-(3-amino-phenyl)-propionitrile in 4.0 ml dichloro-methane and stirred for 12 h. A solution of 324 mg (1.24 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/ethanol 96:4). The obtained material was leached with ether, filtered and dried. Yield 200 mg (37%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:10]2([CH2:15][CH2:14][NH:13][CH:12]([C:16]([NH:18][C:19]3([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)=[O:17])[CH2:11]2)[CH2:9]1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][N:13]1[CH2:14][CH2:15][C:10]2([CH2:9][CH2:8]2)[CH2:11][CH:12]1[C:16]([NH:18][C:19]1([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:17]
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3cccc(C(F)(F)F)c3)CC4)CC2)cc1
Yield: 113.4 %

Procedure:
The title compound (D125) (60.7 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-(6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (single unknown enantiomer) (D90) (50 mg, 0.11 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.020 ml, 0.12 mmol). (Cs2CO3:2 eq; reaction time: 4 hrs; reaction temperature: RT.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][OH:24])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2COS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
[3-(2-Hydroxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.355 g, 1.0 mmol) and triethylamine (0.21 mL, 1.5 mmol) were combined in CH2Cl2 (7.2 mL) and cooled to 0° C. Methanesulfonyl chloride (0.09 mL, 1.1 mmol) was added, and the reaction was stirred for 3 hours. Some starting material was still seen by analytical LCMS, so additional methanesulfonyl chloride (0.04 mL) and triethylamine (0.07 mL) was added at 0° C., and the reaction was stirred for another 2 hours. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:7]=1[CH2:13][CH2:14][C:15]2=[O:17]
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c(Cl)cc(Cl)cc21
Yield: 74.6 %

Procedure:
Thionyl chloride (36.9 g) was added dropwise at 40° C. to a solution of 3-(2,4-di-chlorophenyl)propionic acid (43.8 g) in methylene chloride (200 ml). After reaction was complete, excess thionyl chloride and the solvent were removed by distillation. The oily residue was added dropwise at 40° C. to a suspension of aluminium chloride (53.3 g) in methylene chloride (200 ml). The reaction mixture was added to dilute hydrochloric acid after 18 hours at 40° C. The aqueous phase was separated off and extracted once with methylene chloride (250 ml). The combined organic phases were freed from the solvent. The residue was recrystallized from cyclohexane. 30 g of a colorless solid (m.p.: 115-116° C.) were obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O-:9])=[O:8])[C@@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C[C@@H]([NH3+])C1C=CC=CC=1.Cl.CCO>O>[OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[C@@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C([O-])[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1
Agent: C[C@@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CC[C@H](O)[C@H]1c1ccc(F)cc1

Procedure:
The salt from Step A was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid. [α]D (EtOH)=-19.9 (c=0.675).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([F:20])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:20][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:19]=[CH:18][C:14]=1[C:15](=[O:17])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)N[C@H]2CC[C@H](O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid (40.8 mg, 0.144 mmol) was added NMP (0.5 ml), trans-4-aminocyclohexanol (41.5 mg, 0.360 mmol), Hunig's Base (0.101 ml, 0.576 mmol) and HATU (110 mg, 0.288 mmol) The reaction was stirred at room temperature for 6 hours, followed by LCMS. To the reaction was added 0.5 ml of NMP, filtered, purified by prep LC and lyophilized to give 33 mg of tert-butyl (S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate as the TFA Salt. LCMS m/z 381.1 (M+H)+, Rt 0.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C-:11]#[N:12].[K+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][C:11]#[N:12]
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)cc(CC#N)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
The crude 1-bromo-3-(bromomethyl)-5-methylbenzene obtained from step 5 (188 g, ˜0.71 M) was dissolved in ethanol (470 mL) by warming in an oil bath (50-60° C.). Potassium cyanide (69.57 g, 1.068 M) was added, then distilled water (235 mL). The mixture was heated to reflux and stirred for 3 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was dissolved in dichloromethane and ethyl acetate-hexane (1:20) and loaded onto a silica gel column and eluted with ethyl acetate-hexane (from 1:20 to 1:6) to afford 85 g (53% for 2 steps) of 3-bromo-5-methylbenzyl cyanide (5) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:21])(=[O:20])[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C=O.[C:30]([BH3-])#N.[Na+].O>C(#N)C.CC(O)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:20])(=[O:21])[CH2:17][CH2:16][N:15]([CH3:30])[CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCNC2
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCN(C)C2
Reaction time: 0.25 h

Procedure:
A mixture of ethyl 9-(2,3-dichlorophenyl)-1,1-dioxo-2,3,4,5,6,9-hexahydro-7-methylpyrido-[2,3-f][1,4]thiazepine-8-carboxylate (0.500 g, 1.16 mmole) from Example 8, in acetonitrile (10 mL) was treated with formaldehyde (0.240 g, 37% aqueous solution) and sodium cyanoborohydride (0.062 g, 1.16 mmole). After 15 minutes, 6 drops of AcOH were added and the reaction was stirred for 1 hour. Then, 30 mL of water were added and the reaction mixture was extracted with 3×40 mL of chloroform. The pH was adjusted to 8 after the first extract. The combined organic extracts were dried with brine and Na2SO4 and then treated with 3 mL of triethylamine. After standing for 1.5 hours, the volatiles were removed under reduced pressure and the residue chromatographed (silica gel, 1.5% MeOH, 0.1% NH3 in CHCl3) to obtain the product as an oil which solidified on triturating with ether (0.479 g, 92% yield).
Reaction SMILES: Cl.N1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH:13]=[CH:12]C=CC=1.[F:14]C1C=CC=CC=1C.[OH-:22].[Na+]>O>[F:14][C:3]1[CH:13]=[CH:12][C:6]([CH3:7])=[CH:5][C:4]=1[OH:22]
Reactant: [OH-]
Reactant: Cc1ccccc1F
Reactant: c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(F)c(O)c1
Temperature: 220 °C

Procedure:
To a 500 ml. flask were added 200 grams of pyridine hydrochloride. The flask was fitted with a magnetic stirrer, a reflux condenser, and a nitrogen bubbler. The pyridine salt was heated to about 180° C. to remove any moisture. The salt then was allowed to cool somewhat, and 34 grams (0.243 mole) of the fluorotoluene compound were added. The mixture was heated to 220° C. and maintained there for about 3 hours. The mixture then was cooled, and a large volume of water was added. The reaction mixture then was extracted with several portions of methylene chloride. The methylene chloride extracts were combined, and the solvent was removed in vacuo to obtain a pale yellow product which by nmr analysis indicated the presence of about 5 percent of starting material. The product then was taken up in an excess of 1M sodium hydroxide. The solution was extracted with methylene chloride, and the aqueous layer then was acidified with hydrochloric acid. The acidified portion was extracted with methylene chloride. Evaporation of the methylene chloride extract and distillation of the residue gave 26.6 grams of 2-fluoro-5-methylphenol, b.p.30 86°-93° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4](=[O:9])[C:5]=1[O:6]CC.[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][NH:11][C:3]1[C:4](=[O:9])[C:5](=[O:6])[C:2]=1[NH2:1])[CH3:17]
Reactant: CCOC(=O)CN
Reactant: CCOc1c(N)c(=O)c1=O
Product: CCOC(=O)CNc1c(N)c(=O)c1=O

Procedure:
In the same manner, condensing stoichiometric amounts of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione with ethyl glycinate produces N-(2-amino-3,4-dioxo-1-cyclobutenyl)glycine ethyl ester, m.p. 231°-233° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13](O)[CH2:12][CH:11]2[CH3:21])=[O:9])=[CH:6][C:5]=1[O:24][CH3:25])[CH3:2].[NH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28][CH2:27]3)[CH2:12][CH:11]2[CH3:21])=[O:9])=[CH:6][C:5]=1[O:24][CH3:25])[CH3:2]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCOc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1OC
Product: CCOc1ccc(C(=O)N2c3ccccc3C(N3CCCc4ccccc43)CC2C)cc1OC
Yield: 35.8 %

Procedure:
Starting with 1-(4-ethoxy-3-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (600 mg, 1.76 mmol) prepared in Reference Example 19 and 1,2,3,4-tetrahydroquinoline (703 mg, 5.28 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (288 mg, yield: 36%) as a white crystal. (cis:trans=2:3)